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Characteristics and predictive biomarkers of

drug resistant epilepsy -- study in Georgia

Maia Alkhidze1, Giorgi Lomidze1, Sofia Kasradze1,2, Aleksander Tsiskaridze3

1Institute of Neurology and Neuropsychology, Tbilisi 0186, Georgia.

2Department of Medicine, Caucasus International University, Tbilisi 0141, Georgia. 3Department of Neurology, Iv. Javakhishvili Tbilisi State University, Tbilisi 0179, Georgia.

Correspondence to: Dr. Maia Alkhidze, Institute of Neurology and Neuropsychology, 83/11 Vazha-Pshavela Ave., Tbilisi 0186, Georgia. E-mail: maia-alkhidze@yahoo.com

How to cite this article: Alkhidze M, Lomidze G, Kasradze S, Tsiskaridze A. Characteristics and predictive biomarkers of drug resistant epilepsy -- study in Georgia. Neuroimmunol Neuroinflammation 2017;4:191-8.

Aim: The authors conducted a case-control study to estimate predictive factors for timely identification of patients at higher risk for developing drug resistant epilepsy. Methods: The retrospective case-control study was conducted among people diagnosed as having drug resistant epilepsy (cases) and their controls, identified as having drug-responsive seizures. All participants were admitted to the tertiary Epilepsy Center at the Institute of Neurology and Neuropsychology (Tbilisi, Georgia) during 2011. The data on demographic features and disease characteristics were analyzed. Multiple logistic regression analysis was used to identify independent risk factors for development of intractable epilepsy. Results: A total 334 patients were identified; 84 (34%) met the criteria for drug resistant epilepsy. One hundred and sixty-four age- and gender-matched controls with drug-responsive epilepsy were identified. Relative to the control group, the drug resistant seizure group had increased frequency of perinatal pathology (24% vs. 12%), febrile seizures (22% vs. 12%), seizure frequency at disease manifestation (62% vs. 19%), occurrence of convulsive seizures (84%

vs. 70%), electroencephalo-graph (EEG) epileptiform discharges (94% vs. 77%), polytherapy (90% vs. 12%), multilobar lesions (30% vs. 16%), hippocampal sclerosis (18% vs. 5%), and malformations of cortical development (8% vs. 2%). Multivariate analysis indicated four factors with independent predictive value for development of intractable epilepsy: frequency of seizure, polymorphism of seizure, polytherapy, and epileptiform EEG abnormalities. Key words:

Intractable epilepsy, multivariate analysis, predictive variables

ABSTRACT Article history:

Received: 21 Mar 2017 Accepted: 8 Aug 2017 Published: 27 Sep 2017

Quick Response Code:

Original Article

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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Open Access

DOI: 10.20517/2347-8659.2017.14

Neuroimmunology and

Neuroinflammation

www.nnjournal.net

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The presence of all four factors in combination resulted in a 98% of probability of developing drug resistant epilepsy. Conclusion: Several factors appear to have prognostic value in identifying the risk for drug resistant epilepsy. These factors may prove useful in non-specialized health care settings for timely identification of individuals with elevated risk for drug resistant epilepsy. However, retrospective design and possible recall bias must be considered when interpreting or extrapolating these results.

INTRODUCTION

Epilepsy is one of the most common chronic neurological disease, and affects up to 60 million people worldwide; with no age, racial, social class, national or geographic boundaries[1,2]. Epilepsy causes increased physical and psychosocial morbidity and it imposes a large economic burden on health care systems.

Approximately 2/3 of patients with epilepsy become seizure-free following correct diagnosis and on appropriate treatment with antiepileptic drugs

automated external defibrillator (AED). However,

about 30% of patients with epilepsy continue having seizures despite adequate treatment and tare considered to have drug resistant epilepsy (DRE).

Patients with uncontrolled seizures experience

high rates of injury, psychosocial disabilities, (e.g.

undereducation, unemployment, and impaired

socialization), and psychiatric disturbances[3]. Seizure control is particularly important for prevention of the disability, morbidity, and mortality in people with drug resistant epilepsy.

According to the International League Against

Epilepsy (ILAE) DRE has been defined as the “failure

of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules

(whether as monotherapy or in combination) to

achieve sustained seizure freedom”[4].

DRE usually requires treatment with higher doses of

antiepileptic drugs and/or polytherapy, often resulting in adverse effects and leading to poorer quality of

life (QOL)[5]. Some patients appear to have drug resistance, but have not tolerated several AEDs due

to multiple allergic reactions or other adverse effects.

Weight gain caused by antiepileptic drugs (AEDs)

constitutes a serious problem in the management of patients with epilepsy[6]. Also, there is the increased risk for development of reproductive- endocrine disorders and infertility in women with epilepsy on

long-term AED therapy[7]. Fetal exposure to AEDs increases the risk of congenital malformations[8] and neurodevelopmental impairment[9,10] in offspring of women with epilepsy.

Many patients, particularly the elderly, are more sensitive to central nervous system related adverse

effects of AEDs, such as somnolence and cognitive

impairment[11], further compromising effective seizure control.

In cases of DRE as defined by the ILAE[4], neurosurgical intervention needs to be considered, however, surgical intervention is not indicated in all patients[12,13]. In some cases, a ketogenic diet or vagus nerve stimulation should be discussed[14].

About 60-80% of the patients with drug resistant focal epilepsy become seizure free after epilepsy surgery[15] and up to 30% do not require continued AED treatment if DRE is identified on its early stage. It is well accepted,

that early surgical intervention in most cases of drug resistant epilepsy leads to favorable medium to long term outcomes[16]. However, surgical treatment of epilepsy is often underutilized because of delayed referral of patients to the tertiary epilepsy centers[17]. As a result, patients do not receive potentially curable surgical treatment, which leads to increased medical and economical burden of medically economic burden[16,18]. Beyond misconceptions about surgical risks and poor communication between epileptologists and community physicians[17], the lack of clear criteria for early identification of potential drug resistant

cases among primary or secondary health care practitioners is problematic. In such settings, having the clinically meaningful diagnostic and prognostic criteria for early recognition of patients with increased risk of development of drug resistant epilepsy would facilitate timely implementation of non-medicamentous interventions[19].

This is the study in Georgia designed to identify

factors associated with DRE; the results from which may aid health care practitioners in the classification

of patients at a high risk of developing medically intractable seizures.

METHODS

We carried out a case-control study at the tertiary Epilepsy Center of the Institute of Neurology and

Neuropsychology (ECINN), Tbilisi, Georgia, which

is referral center for the patients suspected to have epileptic seizures. All participants having drug

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The medical records of the patients with epilepsy

who were seen in ECINN (Tbilisi, Georgia) and were entered into the “Epilepsy Registry” from January 1 to December 31, 2011, were reviewed

retrospectively. The diagnostic work-up besides included medical history as well as neurological examination, standard electroencephalography

(EEG), and magnetic resonance imaging (MRI).

Beside of this, inclusion in the study required an epilepsy diagnosed by a multidisciplinary team and

good compliance to AED treatment.

The seizures and epilepsies were classified based on

of ILAE criteria[20]. The DRE was defined according to the ILAE consensus criteria for definition of drug

resistant epilepsy[4].

Detailed methodology of selection participants with drug resistant epilepsy (cases) has been described

elsewhere[10].

Age and gender matched individuals, registered in the INN at the same time interval were selected

for control group (164 individuals). Controls had fully controlled seizures (drug-responsive epilepsy-controls) for at least one year prior to inclusion

in the study or a three times longer seizure-free period compared to the period prior to the start of antiepileptic drug treatment, whichever was longer. All patients were previously diagnosed epilepsy with using a similar multidisciplinary approach

(standard EEG, neuropsychological assessment, MRI, epileptological consultation, final decision-making council). Demographic features and disease

characteristics were obtained from medical records of INN retrospectively.

The study protocol was approved by the National Council of Bioethics. In all cases, informed consent was obtained prior to inclusion in the study.

EEG

At least one standard 30 min 21 channel EEG capturing wakefulness or sleep was recorded.

Hyperventilation and photic stimulation was

performed during all EEG recordings.

Focal and generalized interictal epileptiform

discharges (IEDs) and focal slowing were registered. Focal IEDs were defined as sharp waves, focal and

generalized spikes, spike and wave discharges in single or rhythmic runs, focal polyspikes, and generalized polyspikes with secondary bilateral synchrony.

Due to the paucity of ictal events during standard

EEG recordings ictal EEG findings were not included

in the analysis.

MRI

MRI was performed with 1.5T or 3T high field scanners (Magnetom Avanto and Magnetom Verio, SIEMENS, Germany). The epilepsy MRI protocol included T1 (tse) -weighted 3D axial magnetization prepared rapid

gradient echo images with and without intravenous contrast application, with axial and sub-millimetric

slicing coronal T2 (tse)-weighted turbo spin-echo, coronal T2-weighted fast fluid attenuated inversion

recovery, T2*-weighted axial and diffusion weighted pulse sequences, slices thickness-2.0 mm. Coronal scans were oriented in the perpendicular plane to the long axis of the hippocampus.

Statistical analyses were performed with SPSS

version 20. Armonk, NY: IBM Corp. Descriptive statistics with 95% confidence intervals (CI) were

obtained for demographic and clinical variables. Mean and standard deviation were calculated for characterization of central tendencies. Pearson’s Chi squared test was used to determine association

between categorical variables (Fisher’s exact test was used where appropriate). Multiple logistic regressions

with forward stepwise selection were used to identify independent risk factors for drug resistant epilepsy.

Variables that showed significant results or were close to significance threshold in univariate analysis (antiepileptic drug polytherapy, amount of seizures two

years prior to antiepileptic drug initiation, multilobar

MRI abnormalities, epileptiform discharges on EEG,

seizure polymorphism, perinatal abnormalities, convulsive seizures, hippocampal sclerosis or

malformation of cortical development on MRI, history of febrile seizures) were entered into the multivariate

model. The entry criterion was a P = 0.05 and the exit criterion was a P = 0.1. Hosmer-Lemeshow goodness-of-fit and -2 Log likelihood tests were used to examine the final model. Odds ratio with 95% CI[21] and B coefficients were calculated. P < 0.05 was considered

statistically significant.

RESULTS

Clinical data of 334 patients was evaluated and 208

individuals (62%) were seizure-free. For 126 (38%)

patients, at least one seizure was observed within previous 6 months’ period. Among these subjects,

38 cases (30%) were noncompliance to prescribed

treatment and nonepileptic paroxysmal events were

identified in another 4 individuals (3%). Finally 84 persons (66%) met the criteria of drug resistant

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Demographic features and disease characteristics

The mean age of patients with drug resistant epilepsy

was 26.2 ± 12.2 years (range: 4 to 57 years); 56 patients (67%) were female, whereas, 28 (33%) were

male. The mean age for initial seizure was 8.9 ± 7.8

years (range: 1.2 month to 33 years) and the mean duration of epilepsy was 17.2 ± 10.4 years (range: 2 to 43.3 years). Seventy-six patients (90%) with drug

resistant epilepsy cases were receiving more than one antiepileptic drug at the time of evaluation and

this association was statistically significant (P < 0.001) [Table 1]. A median of five different antiepileptic drug

trials, either with a single drug or in combination, were conducted in individuals with drug resistant epilepsy before inclusion into the study. In most patients with drug resistant epilepsy and on monotherapy

carbamazepine (CBZ), valproic acid (VPA) or phenobarbital (PB) was used. Conversely, relatively few patients used lamotrigine or levetiracetam (LEV). The most popular polytherapy combination was CBZ + VPA (18%) and CBZ + LEV (16%).

Among individuals with drug responsive seizures

CBZ, VPA and PB were the most frequently used as

monotherapy regiments.

Overall 52 patients (62%) from cases and 31 (19%) from controls had frequent seizures (i.e. ≥ 1-3/week)

during the first two years of disease manifestation

(P < 0.001) [Table 2].

Seizure types

The majority of patients with drug resistant epilepsy

(80 patients, 95%) had focal seizures with or without

generalized tonic-clonic seizures; one patient with drug resistant epilepsy had only focal seizure without loss of consciousness that did not substantially disrupt

QOL. Convulsive seizures were more frequently

associated with drug-resistant epilepsy compared to individuals with drug responsive epilepsy. Seizure polymorphism was more frequently observed among

drug-resistant epilepsy cases (68; 82%) compared to individuals with drug responsive epilepsy (99; 60%) (P = 0.002) [Table 3].

Seizure semiology

Based on seizure semiology possible seizure focus among persons with drug resistant epilepsy was consistent with frontal, temporal, parietal or other

origins in 23 (27%), 26 (31%), 5 (6%) and 10 (12%) cases respectively. In 19 individuals (23%) seizure

semiology was inconclusive and one patient had

Table 1: Clinical and demographic characteristics of patients with DRE and controls, n (%)

Demographic/disease characteristics DRE (n = 84) Controls (n = 164) P-value

Age (years), mean (SD); [min; max] 26.2 (12.2); [4; 57] 28.5 (12.5); [6; 59]

-Gender (male) 28 (33) 74 (45)

-Febrile seizures 18 (22) 20 (12) 0.052

Perinatal pathology 19 (24) 22 (12) 0.043

Head trauma as an etiology 3 (4) 12 (7)

-Family anamnesis of epilepsy 5 (6) 17 (10)

-Polytherapy 76 (90) 20 (12) < 0.001

DRE: drug resistant epilepsy; SD: standard deviation

Table 2: Seizure frequency at disease manifestation, n (%)

Seizure frequency DRE (n = 84) Controls (n = 164) P-value

1-3/year or less 5 (6) 79 (48)

-1-3/month 27 (32) 15 (9)

-1-3/week 29 (35) 54 (33)

-Everyday 23 (27) 16 (10)

-Frequent (≥ 1-3/week) 52 (62) 31 (19) < 0.001

Infrequent (≤ 1-3/month) 30 (37) 133 (81)

-DRE: drug resistant epilepsy

Table 3: Distribution of types of seizure across study groups, n (%)

Seizure types DRE (n = 84) Controls (n = 164) P-value

Convulsive seizures Convulsive seizures only

Convulsive seizures with non-convulsive attacks (focal/generalized)

69 (84) 2 67 (80)

107 (70) 8 (5) 99 (60)

0.014

Non-convulsive seizures only Absence and/or myoclonia

Focal seizures only (simple and/or complex)

14(17) 1 13 (16)

51(31) 4 47 (29)

-Unclassified 1 6 (4)

-More than one type of seizures 68 (82) 99 (60) 0.002

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generalized seizures. Nearly the same distribution of seizure semiology was observed in the control group

(frontal 22%; temporal 39%), without a statistically significant association.

Etiology of epilepsy

Of the 84 drug resistant epilepsy patients, the etiology

of epilepsy was established to be structuralin 83

(99%). In 1 case genetic etiology was considered.

In the control group focal epilepsy was observed in

146 (89%) individuals, in 12 cases (7%) generalized epilepsy was established and 6 cases (4%) were unclassified. In most cases, (101; 62%) structural etiology was diagnosed. In 12 (7%) patients, genetic etiology was considered and in 51 (31%) etiology

remained unknown. There was no statistically

significant association observed between drug

responsiveness and etiology of epilepsy.

Standard EEG data

Epileptiform activity presented as focal spikes, polyspikes, sharp waves, spike-wave, sharp-wave

discharges, was observed in 79 (94%) of patients with drug resistant epilepsy and in 126 patients (77%) with drug responsive epilepsy (P = 0.001) [Table 4].

MRI findings

MRI investigations were performed in all cases (with the 1.5 or 3 tesla devices). In 26 (31%) patients with drug resistant epilepsy and in 63 (38%) with drug

responsive epilepsy no pathology was revealed. Among them, all cases of generalized epilepsy

(1 person in drug resistant epilepsy group and 12 individuals in control group) were found no lesion by MRI. Multilobar lesions were identified in 25 (30%) patients with drug resistant epilepsy and in 26 (16%)

patients in the control group. In both groups, lesions were mostly located within the frontal or temporal

lobes [12 (13%) and 22 (14%); 15 (18%) and 18 (11%), respectively].

The most frequent MRI pathologies such as

mesial temporal sclerosis, malformation of cortical development and focal cortical dysplasia occurred

significantly were significantly more often occurred

among drug resistant epilepsy patients. In the control

group major findings were brain tumor and

post-stroke encephalomalacia [Table 5].

Multivariate analysis

Variables that showed significant association with drug

resistant epilepsy were entered into the multivariate model. Factors included: frequent seizures during the

first two years since diagnosis of the disease (B =

2.599; P < 0.001), more than one seizure type (B =

1.366; P < 0.014), polytherapy (B = 4.766; P < 0.001) and epileptiform discharges on EEG (B = 1.836; P <

0.017) were retained in final model as independent predictors of DRE. Probability analysis showed that

with all four factors presented, there is a 98% of chance, that case will further become drug resistant. The Table 6 shows probability of DRE development

for various combinations of independent predictors.

DISCUSSION

The main goal of antiepileptic treatment is complete control of seizures without the side effects of anticonvulsants; however, in 30-35% of cases an effective outcome is not achieved because seizures are resistant to anticonvulsant treatment.

Identifying patients at higher risk of drug resistance as soon as possible is particularly important in

epilepsy management. Various predictors of drug resistance have been identified; however, accurate

prediction is still a problem. In our previous study on the cohort in Georgia, 26% of the individuals with epilepsy experienced drug-resistance according to international criteria[22,23]. The results of the current study provide insights regarding possible risk factors associated with drug-resistant epilepsy.

Recent studies have identified several factors that

Table 4: Standard EEG findings in DRE and control group, n (%)

EEG findings DRE (n = 84) Controls (n = 164) P-value

Normal EEG 2 (2) 7 (4)

-Abnormal EEG 82 (98) 157 (96)

-Slow waves 3 (4) 31 (19)

-Epileptiform discharges 79 (94) 126 (77) 0.001

Sharp waves 35 (42) 91 (55)

-Spikes 6 (7) 6 (4)

-Spike-waves (SW) 13 (16) 14 (9)

-SW < 3 Hz 1 -

-SW 3-4 Hz - 2

-SW 4-6 Hz 1 -

-Polyspikes 2 -

-Sharp-slow waves 21 (25) 13 (8)

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may have prognostic significance for the development

of drug resistance; in particular, focal epilepsy and frequent seizures before antiepileptic drug treatment initiation are more often associated with drug resistant epilepsy. The similar results were revealed in our study, where the vast majority of patients with drug resistant epilepsy had focal seizures and high

frequency of seizures during the first two years of

disease manifestation.

Disease manifestation an early age, long duration of

epilepsy, structural/metabolic and unknown etiology, as

well as particular brain abnormalities (mesial temporal sclerosis, malformations of cortical development)

are most commonly associated with drug resistant epilepsy. There is close concordance between these

findings and our study results: multilobar brain lesions were significantly more often identified in people

with drug resistant epilepsy than in patients with drug-responsive epilepsy; similarly, mesial temporal sclerosis and focal cortical dysplasia were more prevalent brain abnormalities in patients with drug resistant epilepsy compared to controls. Those data are consistent with other studies that have shown

higher occurrence of DRE with cortical dysplasia,

mesial temporal sclerosis, and dual pathology[24,25].

Remote head trauma or brain infection, perinatal

pathology, febrile seizures, family history of epilepsy[26], abnormal neurological status and mental retardation[27] lead to elevated risk for development of drug resistance in individuals with drug resistant

Table 5: MRI findings in individuals with DRE and controls, n (%)

MRI finding DRE (n = 84) Controls (n = 164) P-value

Normal 26 (31) 63 (38)

-Abnormal 58 (69) 101 (62)

-Lobar lesion 29 (35) 68 (42)

-Multilobar lesion 25 (30) 26 (16) 0.023

Midline lesion 4 (5) 1

-Infratentorial - 6 (4)

-MTS 15 (18)

With lacunar lesion-1 With encephalomalacia-1

Bilateral-1

8 (5) 0.002

Cortical atrophy 7 (8)

With leukoencephalopathy-1 19 (23)

-MCD 7 (8)

FCD-6 Heterotopy-1

3

FCD - 2 heterotopy -1 0.030.02

Leukoencephalopathy 5 (6) 8 (10)

-Gliosis 5 (6)

With arachnoid cist-1 10 (12)

-Glioneural tumor 4 (5) 1

-Other brain tumors - 11 (13)

-Dysgenesias of the corpus callosum 2 -

-Hypothalamic hamartoma 2 -

-Polimicrogyria 2

With bilateral schizencephaly-1 1

-Lacunar lesion 2 3

-TSC 2 1

-Ulegyria 1 -

-Postoperative cyst 1 -

-Multiple cystic lesions 1 -

-Encephalomalacia 1 20 (23)

-Cerebral hemiatrophy 1 -

-Arachnoid cyst - 7 (8)

-Cavernous angioma - 5 (6)

-Schizencephaly - 2

-Dandy-Walker anomaly - 1

-MRI: magnetic resonance imaging; DRE: drug resistant epilepsy; MTS: mesial temporal sclerosis; MCD: malformation of cortical development; FCD: focal cortical dysplasia; TSC: tuberous sclerosis complex

Table 6: Estimated probability of development DRE according various presentations of predictor variables Variation of factors presented Probability of development of DRE

All four factors 0.979

Frequent seizures*, politherapy, epileptiform discharges 0.922

Frequent seizures, politherapy, seizure polymorphism 0.880

Politherapy, seizure polymorphism, epileptiform discharges 0.774

Frequent seizures, politherapy 0.652

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epilepsy. Also, in our study a history of perinatal pathology was found in patients with intractable epilepsy.

Stable abnormalities on EEG (e.g. persistent focal slowing or frequent focal epileptiform EEG patterns)

are also considered as prognostic markers of poor seizure control. Likewise, in our study, EEG epileptiform abnormalities were observed more often in drug resistant epilepsy patients compared to controls.

Also, consistent with other studies (references), poor seizure control was significantly associated with

seizure polymorphism.

We found polytherapy to be associated with higher probability to development of drug resistant epilepsy.

Similarly, polipharmacy and the number of failed AED (more than four) trials were significant predictors for

drug resistant epilepsy[28].

Age, gender, history of trauma as epilepsy etiology and family anamnesis of epilepsy were not difference between the two groups.

Multivariate analysis

Multivariate analysis showed that frequent seizures

during the first two years of disease manifestation,

polytherapy, seizure polymorphism and epileptiform discharges on EEG are four independent factors associated with drug resistant epilepsy, and in combination, there is up to 98% certainty that case

will be in the rug resistant epilepsy group. Various

combinations of these four variables also increase probability of developing drug resistant epilepsy [Table 6]. This estimation could be used at primary or

secondary neurological settings for timely identification

of patients with raised probability of development of drug resistant epilepsy.

This study has some limitations that should be mentioned. Because of retrospective design of the study data are collected from medical records and study participants that could be less accurate and prone to recall biases. The study is hospital

based thus may be influenced by selection bias,

and extrapolation to the general population may be limited. Small sample size should be considered as well. Polytherapy was shown to be independent risk factor for development of drug resistant epilepsy, however, polytherapy also could be considered as a

result of epilepsy cases where seizures are difficult to control. So, this finding should be interpreted

carefully and predictive value of polypharmacy should be considered as an additional value in

context of other predictive variables.

We identified predictive biomarkers associated

with development of drug resistant epilepsy. This

can be used as a tool for timely identification of

individuals with elevated risk of intractable seizures for further referral for pre-surgical evaluation. This may enhance cost-effective and potentially curative

treatment of patients with DRE, leading to improved QOL and mitigation of social and economic burden

on health care system.

DECLARATIONS Acknowledgments

We are grateful to G. Kutchuchidze, T. Tchintcharauli, T.

Kobulashvili, D. Kvernadze, K. Geladze, M. Khvadagiani

for providing support for the implementation of the

project, and M. Okujava for reviewing the MRIs.

Authors’ contributions

Designed and executed the study, and assisted the writing and editing of the final manuscript: M. Alkhidze,

S. Kasradze

Assisted with the data analyses, and writing of the paper: G. Lomidze

Designed the study and collaborated in the writing and editing of the final manuscript: A. Tsiskaridze

Financial support and sponsorship

The study was performed within the frame of the

Shota Rustaveli National Science Foundation’s Grant “Epidemiology and risk factors of drug resistant epilepsy in Georgia” (Project number DI/40/8-313/11).

Authors GL and SK have received support from the

grant DI/40/8-313/11.

Conflicts of interest

No specific funding source is associated with the

collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication. The remaining authors have no

conflicts of interest.

Patient consent

In all cases, informed consent was obtained prior to inclusion in the study.

Ethics approval

The study protocol was approved by the National Council of Bioethics.

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Figure

Table 1: Clinical and demographic characteristics of patients with DRE and controls, n (%)
Table 4: Standard EEG findings in DRE and control group, n (%)
Table 6: Estimated probability of development DRE according various presentations of predictor variables

References

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